This project is performed in close collaboration with Dr. Kohn at the Developmental Therapeutics Branch and consists of two lines of study. First, we have developed and released several tools for creating and editing MIM diagrams (Luna, Karac et al. 2011; Luna, Sunshine et al. 2011; Chandan et al., 2012). These tools should make it easier for developers to build MIM-related software, users to create and edit MIM diagrams, and also, help bridge differences between features found in MIM and related notations, such as the BioPAX exchange standard (Demir et al., 2010) and the systems biology graphical notation (SBGN) that is developed by an international consortium with our participation (Le Novere, Hucka et al. 2009; van Iersel et al., 2012). Second, we use MIMs as a basis for mathematical modeling of cellular regulatory networks in an effort to shed light on basic feedback mechanisms that modulate cell proliferation. The first network we have investigated describes the regulation of tumor suppressor p53 by Mdm2 and MdmX in response to DNA damage (Kim, Aladjem et al. 2010). In a separate line of study we have created an extended computational model of a mammalian circadian clock centered on the the nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase SIRT1 (Luna, Aladjem and Kohn, 2013). This model emphasizes the roles of chromatin remodeling and metabolic pathways on the regulation of circadian rhythms. Simulation studies using the molecular interaction network included in the model were able to recapitulate circadian behavior and create a model in which phase shifting of the circadian clock occurs in response to genotoxic stress.. Development and analysis of this model will provide insights into the regulation of circadian rhythms and the potential role of SIRT1 in cancer biology. In the future we aim to combine these studies with experimental characterization of cell cycle regulatory networks that modulate DNA synthesis and affect cell growth. Results from these studies may also add to knowledge on the role of circadian rhythms on the toxicity and activity of therapeutics, including common cancer drugs.